c-Myc regulates RNA splicing of the A-Raf kinase and its activation of the ERK pathway
A-Raf kinase can inhibit apoptosis by binding to the proapoptotic mammalian sterile 20-like kinase (MST2). This function relies on expression of hnRNP H, which ensures the correct splicing of a-raf mRNA needed to produce full-length A-Raf protein. Here, we showed that expression of hnRNP H and production of full-length A-Raf is positively controlled by c-Myc. Low c-Myc reduces hnRNP H expression and switches a-raf splicing to produce A-Raf(short), a truncated protein. Importantly, A-Raf(short) fails to regulate MST2 but retains the Ras-binding domain such that it functions as a dominant negative mutant suppressing Ras activation and transformation. Human colon and head and neck cancers exhibit high hnRNP H and high c-Myc levels resulting in enhanced A-Raf expression and reduced expression of A-Raf(short). Conversely, in normal cells and tissues in which c-Myc and hnRNP H are low, A-Raf(short) suppresses extracellular signal regulated kinase activation such that it may act as a safeguard against oncogenic transformation. Our findings offered a new paradigm to understand how c-Myc coordinates diverse cell functions by directly affecting alternate splicing of key signaling components.
|Authors||Rauch, J.; Moran-Jones, K.; Albrecht, V.; Schwarzl, T.; Hunter, K.; Gires, O.; Kolch, W.;|
|Publisher Name||CANCER RESEARCH|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/pubmed/21512137|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/11279|